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Targeting Tau in Alzheimer's

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Alzheimer's disease is notoriously difficult to treat, and there's no cure on the horizon. Researchers, though, have deciphered specific proteins involved in a pathway that plays a role in the disease, and they think those proteins could offer new drug targets that may slow down, or even halt, the progression of Alzheimer's.

Using siRNA to do a whole kinome screen, researchers from the Translational Genomics Research Institute in Phoenix identified three proteins that lead to the disintegration of neural connections. They are now working on identifying compounds that target those proteins and then testing them in mouse models. "I think we found some strong candidates for drug targets," says Travis Dunckley, an associate investigator in the neurodegenerative unit of TGen and senior author of the study, which was published in BMC Genomics.

The three proteins that Dunckley and his colleagues identified are involved in the phosphorylation of tau, a protein known to be involved in many neurodegenerative diseases. The phosphorylation of tau in Alzheimer's leads to the unraveling of the microtubules that serve as transport elements between neurons and synapses. Tau is an important component of those microtubules, binding to and stabilizing them. But when it is phosphorylated, tau instead binds to itself, forming neurofibrillary tangles. This causes the microtubules to disintegrate, eventually leading to the death of the synapses and neurons.

The primary pathway that leads to Alzehimer's disease is thought to be an accumulation of amyloid plaque in the brain, and much of the current research targets that pathway. However, Dunckley and his team are instead targeting the tau pathway, which is also implicated in Alzheimer's, dementia, and other neurodegenerative diseases.

The researchers first developed an antibody assay to detect tau levels in both its phosphorylated and unphosphorylated states to get baseline measurements. They then used RNA interference to determine which kinases affected tau. They added siRNA targeted toward each of the 572 different kinases. Each siRNA specifically inhibited the expression of one of the target kinases. "You have effectively created a cell line that lacks function of a single target gene," Dunckley says. "Then we use that as a tool to screen for genes that alter the level of tau."

Two of the three proteins they identified are involved in the tau phosphorylation pathway, while the third is involved in tau expression.

Now that Dunckley has identified candidate proteins, he and his team are working on developing compounds that knock out those proteins and are also trying to figure out -whether it will be important to target all three proteins, or if targeting one will be sufficient. "We don't know exactly what the pathways are, whether it's three different pathways or three genes in one pathway," he says.

Dunckley says he has had some promising results on identifying compounds and is now testing those compounds in vitro as well as in mice to see how they affect tau levels. In the mouse studies, he is using RNAi to inject the compounds into specific brain regions to see how they affect tau phosphorylation.

Aside from Alzheimer's, the work could have implications for other neurodegenerative diseases, which are also characterized by excessive tau phosphorylation. Ultimately, Dunckley thinks that targeting the tau pathway won't cure the disease, but could prevent further memory loss.

It is likely that the timing of the diagnosis will determine how effective the treatment is. If Alzheimer's can be diagnosed early, before significant function is lost, he thinks treatment could be extremely effective. "Given the state of treatments for Alzheimer's, having one that works a little is way better than what's available at the moment," he says.

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